Synapsin is a protein initially discovered and characterized as a target for cyclic AMP and Ca/calmodulin-regulated protein kinases that is concentrated in nerve endings and is localized on the surface of small synaptic vesicles. Synapsin shares antigenic sites and some local regions of homology with erythrocyte protein 4.1, although these proteins in general are quite different in sequence. Protein 4.1 and synapsin share several local regions of homology with erythrocyte spectrin alpha subunit. Protein 4.1 and synapsin may be related to each other through a common relationship with spectrin. Synapsin binds to synaptic vesicles and membrane sites with a Kd of 0.01-0.02 microM and associates with a Kd of 0.5-4 microM to spectrin, microtubules and neurofilaments in in vitro assays. Synapsin interconnects synaptic vesicles to membranes, and this activity is inhibited by phosphorylation with Ca/calmodulin-dependent protein kinase. Synapsin may have a role in neurons as a structural protein capable of interconnecting small synaptic vesicles with a number of proteins, including spectrin, microtubules, neurofilaments, and membrane sites. A physiological function of synapsin could be as a vesicle-organizing protein that mediates calcium-regulated association of vesicles with cytoskeletal proteins during axonal transport and attaches vesicles to active zones in nerve endings.